Citations

Abstract Introduction: Monitoring minimal residual disease (MRD) is critical in multiple myeloma (MM) to predict outcomes and guide therapy. Traditional bone marrow (BM) aspirates for MRD detection are invasive and limited by sample quality. We therefore explored cell-free DNA (cfDNA) fragmentation as a less invasive alternative for MRD detection. Methods: We performed 30-40X whole-genome sequencing (WGS) on peripheral blood cfDNA from 45 MM patients, collecting baseline (n = 45) and follow-up samples (n = 98) from eight Canadian sites (M4 and IMMAGINE studies) and one U.S. site (SPORE study), plus 25 healthy controls. Samples were collected post-induction therapy (n = 13), 100 days post-autologous stem cell transplantation (ACST, n = 36), and during maintenance therapy (n = 49). Multiparameter flow cytometry (MFC) MRD testing was conducted on 77 samples. We evaluated insert size metrics and MM-specific chromatin accessibility (from Ordoñez et al., 2020) using Griffin (described in Doebley et al., 2022). Results: Baseline samples had a higher proportion of short fragments (20-150 bp) than follow-up samples (p = 0.0037) and healthy controls (p = 0.019). A fragment score (FS) based on weighted fragment distribution (per Vessies et al., 2022) was highest at baseline (mean = -0.384), followed by MRD-positive (mean = -0.495) and MRD-negative (mean = -0.550) samples. MRD-negative FS was lower than baseline samples (p < 0.001) but higher than healthy controls (mean = -0.639; p = 0.016). Baseline samples had lower coverage at MM-specific chromatin regions than MRD timepoints (p < 0.05; baseline mean = 0.982; MRD-positive = 0.989; MRD-negative = 0.994; healthy = 0.993), suggesting higher transcriptional activity pre-treatment. MRD-negative samples had higher coverage than MRD-positive cases (p < 0.01). Using logistic regression, we assessed the predictive performance of FS and coverage at MM-specific sites. FS alone achieved an AUC of 0.632 (sensitivity [SN] 39.4%, specificity [SP] 92.1%, accuracy [AC] 67.6%). Coverage yielded an AUC of 0.681 (SN 75.8%, SP 60.5%, AC 67.6%). Combining FS and coverage at MM sites improved performance (AUC = 0.734; SN 48.5%, SP 92.1%, AC 71.8%). We next evaluated whether adjusting the BM tumor cell percentage cutoff by MFC could improve performance. At 0.017% (1 in 5, 789 cells) for MRD positivity, the combined model’s accuracy reached 83% with an AUC of 0.757 (SN 17%, SP 97%). Conclusions: cfDNA fragmentomic analysis achieved high specificity (92-97%) in detecting MRD, providing a less invasive alternative to facilitate serial monitoring. While sensitivity remains an area for improvement, the high specificity of cfDNA makes it valuable for confirming MRD negativity and reducing invasive procedures. Future efforts aim to enhance sensitivity by integrating additional fragmentomic features. Citation Format: Dor D. Abelman, Jenna Eagles, Aimee Wong, Saumil Shah, Stephanie Pedersen, Stephenie Prokopec, David S. Scott, Sarah Bridges, Darrell White, Irwindeep Sandhu, Kevin Song, Esteban Braggio, Alli Murugesan, Anthony Reiman, Suzanne Trudel, Trevor J. Pugh. Tumor-independent monitoring of minimal residual disease in multiple myeloma using cfDNA fragmentomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3250.

Introduction: Physical activity (PA) has been identified as a protective factor for dementia, but the mechanisms linking PA to brain health are unclear. To elucidate potential pathways linking PA to brain health, we tested the hypothesis that higher levels of late-life PA are associated with a lower burden of Alzheimer’s disease (AD) pathology, cerebrovascular disease, and neurodegeneration measured through brain imaging and plasma biomarkers. Methods: ARIC-NCS participants without dementia in 2011-13 and with measures of PA, 3T brain magnetic resonance imaging (MRI), and stored plasma samples were examined (n=1,771; mean age: 76.5 years; 40.5% male; 27.6% Black). Participants were classified as meeting or not meeting 2018 aerobic PA guidelines based on a standardized interviewer-administered questionnaire. MRI biomarkers included white matter hyperintensity (WMH) volume (cm 3 ), total brain volume (TBV) (cm 3 ), and cortical thickness (CT) (mm). Plasma biomarkers of the ratio of amyloid beta 42 to 40 (Aβ42/Aβ40), phosphorylated Tau-181 (p-Tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were measured using Quanterix Simoa immunoassays. All biomarkers were standardized to measures in 2011-13 to facilitate comparisons. Covariate-adjusted linear regression models estimated cross-sectional associations of PA with MRI or plasma biomarkers. Covariate-adjusted linear mixed effects models quantified associations of PA with the 5-year rate of change in a subset of participants with MRI (n=669) or plasma (n=651) biomarkers at both baseline and follow-up from 2011-19 (median follow-up: 5.4 years). Results: Meeting versus not meeting aerobic PA guidelines was cross-sectionally associated with lower volumes of WMH (β = -0.16, 95% CI: -0.25, -0.07), higher TBV (β = 0.09; 95% CI: 0.05, 0.13), and lower plasma NfL (β = -0.102, 95% CI: -0.184, -0.021) ( Figure ). Late-life PA was not associated with 5-year rates of change in MRI or plasma biomarkers. Conclusions: Late-life PA was cross-sectionally associated with less neurodegeneration and cerebrovascular disease. Associations with 5-year changes in imaging and plasma biomarkers of AD pathology, cerebrovascular disease, or neurodegeneration were not statistically supported. Longitudinal biomarker studies with wearable devices that quantify other daily intensity-based movement metrics (e.g., light PA) and larger sample sizes are needed to further examine mechanisms linking PA to brain health.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Abstract Selective activation of smaller diameter over large diameter nerve fibers represents a broad challenge in the electrical modulation of neural activity for clinical applications. For example, off-target activation of motor nerve fibers has been implicated in several failed vagus nerve stimulation (VNS) clinical trials by precluding achieving current amplitudes sufficient to activate the therapeutically targeted small diameter fibers. In this study, we evaluated the use of high-frequency (HF) stimulation to block unwanted activation of large diameter fibers evoked by traditional low-frequency (LF) VNS in a large animal (swine) model. We demonstrate that HF can eliminate specific unwanted LF-evoked components from neural recordings with high selectivity – along with their associated off-target physiological responses - while preserving the activation of smaller diameter fibers driving intended physiological responses. Conversely, block of the smaller diameter fibers was only observed at HF amplitudes much higher than amplitudes commonly used for HF block clinically. We found that in addition to blocking the LF-evoked compound action potential, lower HF amplitudes also drive asynchronous activity which can easily be overlooked. Only at high amplitudes did HF block LF-evoked activation without concomitant asynchronous activation. These data have numerous implications for existing and future LF and HF block neuromodulation therapies.

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

Abstract Aim Reversal of diverting loop ileostomy (DLI) traditionally occurs at ≥12 weeks after formation. Early closure has been performed in attempts to reduce DLI‐associated morbidity. Therefore, the aim of this study was to determine whether time to stoma reversal impacts postoperative morbidity. Method A retrospective review was conducted using institutional‐level American College of Surgeons National Surgical Quality Improvement Program data for adult patients who underwent DLI closure between January 2012 and December 2021 across a multistate health system. Time to DLI closure was stratified into three groups: ≤12, 12–24 or 24–36 weeks. Additional data were obtained from the electronic medical record. The primary outcome was major morbidity after DLI closure. Results A total of 482 patients underwent DLI closure. Eighty four patients underwent closure at ≤12 weeks (17.4%), 300 at 12–24 weeks (62.2%) and 98 at 24–36 weeks (20.3%). The most common diagnosis at DLI formation was cancer ( n = 211, 43.8%). Patients in the ≤12 weeks closure group more commonly had ulcerative colitis or diverticular disease and a lower American Society of Anesthesiologists class than patients with closure at 24–36 weeks ( p < 0.05). There were no significant differences in complication severity, overall major morbidity or its individual components amongst the time to DLI closure groups. There were no differences in anastomotic leaks or need for laparotomy. On multivariable analysis, immunosuppressive therapy and preoperative haematocrit <30% were significant risk factors for major morbidity after DLI closure. Conclusion Major morbidity did not differ by time to DLI closure group, indicating that closure at ≤12 weeks is safe in selected patients.

Abstract Quantitative computed tomography (CT) enables the measurement of biophysical processes characterized by morphology, composition, flow, and/or motion to aid in clinical diagnosis and intervention. Since its initial application for determining bone mineral density for skeletal fragility assessment, quantitative CT has continued to evolve alongside CT’s technological advancements. A key challenge facing quantitative CT is the lack of standardization pertinent to image acquisition, reconstruction, and image analysis. With the introduction of spectral CT involving dual-energy approaches and photon-counting detectors (PCD), we are now able to obtain detailed information regarding mass densities of endogenous and exogeneous materials. Furthermore, energy-resolved CT yields spectral image types (eg, virtual monoenergetic image) that are, in principle, independent of tube potential and patient size. This paves the way for workflow standardization and helps improve the consistency and reproducibility of CT-derived measurements. In this article, we review clinical applications of quantitative CT, discuss key challenges associated with quantitative CT and its adoption into routine practice, and outline the unique benefits ushered by new CT technologies such as PCD-CT towards improving quantitative imaging.